Catecholamines Flashcards
(63 cards)
1
Q
What is the main excitatory and main inhbitory neurotransmitter?
(2 marks)
A
Glutamate is main excitatory
GABA is main inhibitory
2
Q
What are the small molecule neurotransmitters?
A
- Monoamines and acetylcholine
3
Q
What do the monoamines consist of and what is the name of this group?
(4 marks)
A
Catecholamines:
- Dopamine
- Epinephrine (adrenaline)
- Norephineprine (noradrenaline)
4
Q
What do all the catecholamines have in common?
(2 marks)
A
- All ave a catechol nucleus and amine group
5
Q
What does the adrenal medulla secrete?
(2 marks)
A
- Epiphrine and norepinephrine
- Act as hormones in blood stream
6
Q
How does the process of catecholamine synthesis begin?
(3 marks)
A
- AA tyrosine ⇒ undegoes first hydroxylisation forming tyrosine hyroxylase (TH)…
- TH used in dementia to measure function of dopaminergic neurons in basal ganglia
- …and an aromatic amino acid decarboxylate (AADC) [precursor of DA] and is found in eurons that make DA
7
Q
What is DOPA converted into?
(2 marks)
A
- A catecholamine by dopamine ß hydroxylase (DBH)
- And then into dopamine which is the direct precursor of norepinephrine
8
Q
Where is PNMT and what is it?
A
- Expressed in adrenal gland and can convert NE into EPI
9
Q
At the DA and NE level what enzymes are expressed in their catabolic pathways?
A
- MAO, COMT: produce different metabolites to be released in extracellular fluids throughout the brain
10
Q
Excessive concentration of which molecules show that a patient has taken cocaine?
(2 marks)
A
- HVA and VMA - produced from DA being catalysed by MAO/COMT
- MHPG - produced by NE being catalysed from PNMT
11
Q
Whatis the rate limiting enzyme in DA and NE synthesis?
A
Tyrosine Hydroxylase
12
Q
How is the activity of TH regulated?
(2 marks)
A
- High catecholamine levels will inhibit TH (negative feedback)
- Rate of cell firing - when neurons fire at high rate TH is stimulated and catecholamine synthesis accelerates
13
Q
How can catecholamine synthesis be increased?
A
Administration of pre-cursor i.e. L-DOPA (used to treat PD)
14
Q
What does α-methyl-para-tyrosine (AMPT) do?
A
Blocks TH preventing the overall catecholamine synthesis
15
Q
What happens to catecholamines after synthesis?
A
Packaged into a vesicle, and the vesicular monoamine transporter (VMAT) recognises the monoamines
16
Q
What does the drug reserpine do to VMAT?
(2 marks)
A
- Blocks it
- And therefore increases accumulation of DA by causing paradoxical behaviourla effects
17
Q
What can be seen when DA and NE are broken down?
A
Not in vesicle, so can see sedation and depression
18
Q
How is catecholamine released?
A
By exocytosis when nerve impulse reaches terminal
19
Q
What drugs cause release of catecholamines independently of cell firing?
(3 marks)
A
- Amphetamine and Metaphetamine
- in animal models see increased locomotor activity and stereotyped behaviours
- Continuum of behavioural action stems from increasing stimulation of DA receptors in nucleus accumbens and striatum
20
Q
What is catecholamine release inhibited by?
(6 marks)
A
-
Autoreceptors:
- specific for each NT
- largely located at pre-synaptic terminal ⇒ enhance opening voltage gated K+ channels
- shortens duration of action potentials and reduces Ca2+ influx
- and vesicle exocytosis aas membrane is hyperpolarised
- Somatodendritic autoreceptors: inhibit NT release indirectly by reducing rate of firing of cell
21
Q
What is Ki ?
(2 marks)
A
- Dissociation constant
- Equilibirum constant that specifically involves measure of prosperity of dissociation of a complex molecule into its subcomponents
22
Q
What is Km ?
A
Substrate concentration at which reaction rate is half of its maximal value
23
Q
What receptors do DA and NE contain?
(2 marks)
A
- DA - D autoreceptors (1-5)
- NE has α and ß autoreceptors
24
Q
What do autoreceptor anatgonists do?
A
Enahnce rate of release of catecholamines
25
What do α2 agonists and anatagonists do after ingestion of opioids?
(2 marks)
* α2 agonists: e.g. **clonidine** - used to treat symptoms of opioid withdrawal
* α2 antagonists: e.g. **yohimbine** - blocks autoreceptors and **increases** **noradrenergic cell firing** and NE release. Provokes withdrawal symptoms and opioid craving
26
How is DA and NE reuptaken?
| (3 marks)
1. DA and NE **removed from synaptic cleft** to nerve terminal by specific transporter proteins
2. Molecules **re-packaged** inot vesicles or broken down
3. Transporter mediated uptake plays vital role in normal regulation of catecholamine activity
27
What happens in mutant mice with no DA or NE transporters?
(2 marks)
* No DA transporters - don't respond to psychostimulants i.e. cocaine and amphetamines
* No NE transporters - increased sensitivity to same drug
28
Give some examples of drugs that block transport and their function.
(3 marks)
* **Tricycic antidepressants**:
* inhibit reuptake of both NE and serotonin
* **Reboxetine (edronax):**
* antidepressant and atomoxetine - drug used to treat ADHD
* **Cocaine****:**
* inhibits reuptake of ALL monoamine transmitters: DA, NE & 5-HT
29
How are DA and NE broken down?
| (4 marks)
By enzymes COMT and MAO which produces:
* DA metabolite - breakdown product is homovanillic acid
* NE metabolites - MHPG in brain and vanillymandelic acid (VMA) in PNS
^^ metabolites enter CSF and blood stream and eliminated with rine
30
What drugs inhibit breakdown enzymes?
| (4 marks)
* MAO inhibitors: i.e. phenolzine or tranylcypromine
* Used to treat clinical depression
* COMT inhibitors: i.e. entacapone and talcapone
* enhance effectiveness of L-DOPA in treating PD by preventing breakdown of DOPA
31
What is the classification system of cells for DA and NE?
(2 marks)
* Cell groups A1-A7 are **noradrenergic**
* Cell groups from A8 to A16 are **dopaminergic**
32
What cell group does the nigorstiatal tract contain?
(3 marks)
* Axons from A9 cell group in subtantia nigra - extends to caudate-putamen or striatum
* Nigrostriatal tract is **dopaminergic pathway** and connects SNc to dorsal striatum
* Critical in production of movemnt in basal ganglia motor loop
33
Where is the A10 cell group located and what does it give rise to?
(3 marks)
In _VTA_ and gives rise to 2 pathways:
* **Mesocorticocal dopamine pathway:** from VTA to prefrontal cortex
* **Mesolimbic pathway:**from VTA to different structures in limbic system
34
Are the receptors for DA metabotropic or ionotropic?
Metabotropic and interact with G proteins and function via secondary messengers
35
What receptor antagonists are almost all anti schizophrenic drugs?
D2 receptor antagonists
36
What is the dopaminergic receptor famil consist of?
D1 and D5 are similar
D2, D3 , and D4 are seperate family
37
Why is it more common to find cells that obly express either D1/D2 receptors and not both?
They act in opposite fashions - uncommon to find cell that expresses both
38
How does a D1 receptor affect the production of cAMP?
* D1 receptor is coupled to Gs and so it is **positively coupled to adenyl cycalse** and **increases the production of cAMP**
39
How does the D2 receptor affect the production of cAMP?
Coupled to either **Gi or Go** and so is acting **negatively on adenyl cyclase** and therefore tends to reduce production of cAMP
40
How do D2 receptors regulate membrane K+ channels?
1. D2 receptor stimulation activates **G protein** that enahnces K+ channel opening and causes **hyperpolarisation** of cell membrane and **decreases excitability and firing rate of cell**
41
What are different agonists for D autoreceptors and what do they do?
(4 marks)
* SKF 38393 - for D1 receptors
* Quinpirole activates D2 and D3 receptors
* Apormophine agonist stimulates both D1 and D3 receptors:
* causing behavioural activation simmilar to those seen in cocaine and amphetamines
42
What do DA receptor antagonists do?
| (3 marks)
* Suppress exploratory and locomotor behaviour
* At higher doses such durgs can result in catalepsy and **lack of spontaneous movement**
* This is usually associated with D2 receptor blockers i.e. haloperidol
43
What has been seen in DA transporter KO mice?
(2 marks)
- Extremely hyperactive as DA **cannot be removed from synaptic cleft**
- Mice tested in photocell apparatus - no. of photobeam breaks was recorded every 20 mins and all group showed gradual habituation
44
What do KO of D1 and D2 receptor mice show?
(4 marks)
* D1 KO show deficits in cognitive tasks
* D2 KO show **impairment in spontaneous movement**, co-ordination and posture control
* Double KO of both D1 and 2 show **reduced** or **no increase in locomotion**
* Double KO of both D1 and D2 receptor genes leads to **fatality** during 2nd or 3rd week of life
45
What do D4 receptor mice KO show?
Mice are **hypersensitive to metamphetamines and cocaine**
46
How can rodents develop behavioural sypersensitivity?
From the adminstration of a D2 receptor antagonist i.e haloperidal - given on a long term basis
47
What are the central and peripheral components of the noradrenergic system?
(2 marks)
* **Central:** cell bodies are in the brainstem and ascending fibres go to forebrain structures
* **Peripheral:** part of sympathetic nervous system
48
Where are NE neurons located in the brain?
(3 marks)
* Found in **pons and medulla**
* **Locus coerulus (LC) in pons:** dense collection of NE neurons corresponding to A6 cell group
* Fibres extend to nearly all areas of forebrain and cerebellum and spinal cord
49
How can NE reach organs in the body?
| (2 marks)
* Released from **sympathetic noradrenergic neurons** at synapse - like contacts with cardiac cells
* Released from **adrenal glands** and travel in bloodstream to heart
50
Are adrenergic receptors metabotropic or ionotropic? What are the existing subtypes?
(4 marks)
* Metabotropic
* subtypes:
* α1/2 receptors and ß receptors
* α2 receptors - reduce synthesis of cAMP
* α1 receptors - operate via phosphoinositide secondary messenger system
* ß1/2 - adrenoreceptors stimulate adenyl cyclase and enhance synthesis of cAMP
51
What is the central noradrenergic system involved in?
(2 marks)
Arousal, cognition, consolidating memories of emotional experiences
LC projects to prefrontal cortex which plays a role in attention and working memory
52
What happens after the activation of α1/2 receptors in the prefrontal cortex?
(2 marks)
* α1 receptor activation - deleterious affect on cognitive function
* α2 receptor activation - activated by using selective agonists i.e. clonidine - enhances working memory
53
How does NE faciliate PFC functon and cognitive tasks in normal conditions?
Activates **adrenoreceptors** there
54
Which α receptor does NE have a lower affinity for in the prefrontal cortex?
α1
55
What is increased NE associated with?
Stress or increase in α1 receptor activation - can lead to cognitive impairment
56
Why do odents show increased time awake after adminstration of either α1 or ß-adrenergic agonists?
(2 marks)
* LC neurons fire more rapidly during waking than asleep
* Noradrenergic pathways from LC to **medial septal and medial preoptic areas** are involved in wakefulness
57
What molecules are impliacted in consolidation of emotional memory and how is memory consolidation evaluated?
* NE, EPI and glucocorticoid hormones
* Measured using 'one-trial passive avoidance learning paradigm'
58
Why are EPI modulates used in treatment of non-psychiatric conditions?
Due to widespread distribution of adrenergic receptors in peripheral organs
59
What is used to treat asthma?
(also in COD)
* ß2 agonists e.g. albutenol in an inhaler
60
What is used to treat hypertension?
| (4 marks)
* α1 - antagonist **prazosin** and ß - anatognist **propanolol**
* Prazosin **blocks α1-receptors** that cause blood vessel constriction
* Propanolol **blocks ß-receptors** in the heart **reducing its contractile force**
* ß1 is main subtype in the heart and its seleciev antagonists i.e. metoprodol have fewer side effects
61
What are ß antagonists used to treat?
Anxiety - reduce phsyical symptoms e.g palpitations
62
What are α2 agonists used to treat?
* **Hypertension** - as inhibit activity of **sympathetic nervous system** while stimulating parasympthatetic NS
63
What is dexmedetomidine?
| (2 marks)
* α2 agonist
* When combined with sedative i.e. anxiolytic and analgesic has pain reducing and anti anxiety effects
